Methods for organic synthesis of compound are generally divided largely into a solid phase method and a liquid phase method. The solid phase method is advantageous in that isolation and purification after the reaction can be performed by only washing of resin. However, the solid phase method is problematic in that it essentially includes a non-homogeneous phase reaction, reaction agents and reagents need to be used in excess amounts to compensate for the low reactivity, and tracking of reaction and analysis of the reaction product on a carrier are difficult.
In an attempt to perform reaction in a homogeneous liquid phase while utilizing the advantage of the solid phase method in that isolation and purification after the reaction can be performed by filtration and washing alone, a method of isolating a particular component dissolved in a liquid as a solid has been used. This is because precipitation of a particular component alone facilitates isolation and purification after reaction.
A particular component dissolved in a solution can be precipitated only when predetermined conditions are satisfied, such as chemical properties, property and relationship with solvents of the compound.
However, determination of precipitation conditions requires trial and error and experimental searches in most cases. In liquid phase synthesis, moreover, some compounds to be synthesized are insoluble in organic solvents used for extraction or show low solubility therein, which necessitates confirmation of the property of each compound to search for isolation and purification methods therefor. Particularly, when sequential and multistep synthesis reactions are required as in peptide synthesis and the like, since isolation and purification conditions such as precipitation, extraction and the like need to be determined based on the properties unique to the compound synthesized in each step, long time and high cost are required.
In addition, the general liquid phase synthesis process, which has been known for long, requires more complicated operations than the solid phase methods; however, it is advantageous in that intermediate peptide can be purified by extraction wash, isolation and the like after condensation reaction. On the contrary, in extraction wash with nonpolar organic solvents and acidic or basic aqueous solutions, precipitation, transfer to aqueous layer side together with impurity and the like easily occur depending on the chain length and property of peptide, which renders extraction into the organic layer side difficult. Particularly, for a peptide with a short chain having a carboxamide-type C-terminal (—CONHR: R is a hydrogen atom, an alkyl group or an aralkyl group), the difficulty in extraction into an organic layer as mentioned above becomes noticeable since it acquires high hydrophilicity and the like. The peptide having a carboxamide-type C-terminal is generally used for peptide pharmaceutical products for the reasons of stability and improved activity in the body and the like, and causes problems in the liquid phase synthesis of such peptide.
On the other hand, a method using a protecting group (anchor) capable of irreversible change of a dissolution state and an insolubilized state (precipitated state) of a particular component according to the varying solvent composition has been developed. Using such anchor, a compound to be the isolation object can be selectively precipitated from a homogenous solution state.
For example, patent document 1 and non-patent document 1 disclose methods including developing an anchor by introducing a long chain aliphatic group into a benzyl alcohol type compound (see the following structure), dissolving and reacting the anchor in a halogen solvent, and precipitating a reacted product with polar organic solvent such as methanol or acetonitrile to allow peptide chain elongation.

However, since the anchor is a benzyl alcohol type compound, even when the anchor is used as a protecting group of a C-terminal or side chain carboxyl group, the group returns to a free carboxyl group after deprotection. Therefore, the anchor cannot be used as a C-terminal or side chain anchor aiming at synthesis of peptide with carboxamide-type C-terminal.